Spinal cord injury involves the loss of gray matter and the interruption of white matter tracts at the level of injury. For thoracic injuries, the deficits resulting from white matter damage far outweigh those from the loss of gray matter. The objectives of this proposal are threefold. First, to delineate the potential contributions that gray matter and white damage make to the deficits that results following spinal cord injury using two different but proven animals models, excitotoxicity (intraspinal kainate injection) and demyelination (ethidium bromide/x-irradiation). Secondly, to use the model of gray matter damage to study neuron replacement strategies using a variety of neural stem cells, including neuron-enriched populations derived from embryonic rat spinal cord. Part of this second objective is to compare the neuronal differentiation and range of terminal phenotypes achieved by populations of cells following transplantation and in culture. Finally, the information gained in the first two aims will be used to develop targeted strategies to replace gray matter following contusion injuries of the lumbar enlargement. This project will either provide evidence that neuron replacement strategies an provide significant functional benefits to the injured spinal cord or will more clearly define the problems that must still be overcome to reach that goal.